ICOSL+ plasmacytoid dendritic cells as inducer of graft-versus-host disease, responsive to a dual ICOS/CD28 antagonist

被引：24

作者：

Adom, Djamilatou ^{[1
]}

Dillon, Stacey R. ^{[2
]}

Yang, Jinfeng ^{[1
]}

Liu, Hao ^{[1
]}

Ramadan, Abdulraouf ^{[1
]}

Kushekhar, Kushi ^{[1
]}

Hund, Samantha ^{[1
]}

Albright, Amanda ^{[1
]}

Kirksey, Maykala ^{[1
]}

Adeniyan, Titilayo ^{[1
]}

Lewis, Katherine E. ^{[2
]}

Evans, Lawrence ^{[2
]}

Wu, Rebecca ^{[2
]}

Levin, Steven D. ^{[2
]}

Mudri, Sherri ^{[2
]}

Yang, Jing ^{[2
]}

Rickel, Erika ^{[2
]}

Seaberg, Michelle ^{[2
]}

Henderson, Katherine ^{[2
]}

Gudgeon, Chelsea J. ^{[2
]}

Wolfson, Martin F. ^{[2
]}

Swanson, Ryan M. ^{[2
]}

Swiderek, Kristine M. ^{[2
]}

Peng, Stanford L. ^{[2
]}

Hippen, Keli L. ^{[3
]}

Blazar, Bruce R. ^{[3
]}

Paczesny, Sophie ^{[1
,4
]}

机构：

[1] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA

[2] Alpine Immune Sci, Seattle, WA 98102 USA

[3] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA

[4] Med Univ South Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2020年 / 12卷 / 564期

关键词：

BONE-MARROW-TRANSPLANTATION; ALLOREACTIVE T-CELLS; INDUCIBLE COSTIMULATOR; GVHD; PREVENTION; ENGRAFTMENT; BLOCKADE; MARKER; DONORS; ROLES;

D O I：

10.1126/scitranslmed.aay4799

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Acute graft-versus-host disease (aGVHD) remains a major complication of allogeneic hematopoietic cell transplantation (HCT). CD146 and CCR5 are proteins that mark activated T helper 17 (Th17) cells. The Th17 cell phenotype is promoted by the interaction of the receptor ICOS on T cells with ICOS ligand (ICOSL) on dendritic cells (DCs). We performed multiparametric flow cytometry in a cohort of 156 HCT recipients and conducted experiments with aGVHD murine models to understand the role of ICOSL+ DCs. We observed an increased frequency of ICOSL+ plasmacytoid DCs, correlating with CD146(+)CCR5(+) T cell frequencies, in the 64 HCT recipients with gastrointestinal aGVHD. In murine models, donor bone marrow cells from ICOSL-deficient mice compared to those from wild-type mice reduced aGVHD-related mortality. Reduced aGVHD resulted from lower intestinal infiltration of pDCs and pathogenic Th17 cells. We transplanted activated human ICOSL+ pDCs along with human peripheral blood mononuclear cells into immunocompromised mice and observed infiltration of intestinal CD146(+)CCR5(+) T cells. We found that prophylactic administration of a dual human ICOS/CD28 antagonist (ALPN-101) prevented aGVHD in this model better than did the clinically approved belatacept (CTLA-4-Fc), which binds CD80 (B7-1) and CD86 ( B7-2) and interferes with the CD28 T cell costimulatory pathway. When started at onset of aGVHD signs, ALPN-101 treatment alleviated symptoms of ongoing aGVHD and improved survival while preserving antitumoral cytotoxicity. Our data identified ICOSL+-pDCs as an aGVHD biomarker and suggest that coinhibition of the ICOSL/ICOS and B7/CD28 axes with one biologic drug may represent a therapeutic opportunity to prevent or treat aGVHD.

引用

页数：15

共 41 条

[41] ST2 blockade reduces sST2-producing T cells while maintaining protective mST2-expressing T cells during graft-versus-host disease [J].

Zhang, Jilu ;

Ramadan, Abdulraouf M. ;

Griesenauer, Brad ;

Li, Wei ;

Turner, Matthew J. ;

Liu, Chen ;

Kapur, Reuben ;

Hanenberg, Helmut ;

Blazar, Bruce R. ;

Tawara, Isao ;

Paczesny, Sophie .

SCIENCE TRANSLATIONAL MEDICINE, 2015, 7 (308)

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